Aortic aneurysm is a chronic degenerative disease characterized by segmental weakening and dilatation of the vascular wall.
Aortic aneurysms are commonly classified according to their anatomical location. Thoracic aortic aneurysms (TAAs) involve the ascending aorta, arch or descending aorta; Aneurysms of the ascending thoracic aorta most often result from cystic medial degeneration, which appears histologically as smooth muscle cell dropout and elastic fiber degeneration. Medial degeneration leads to weakening of the aortic wall, which in turn results in aortic dilatation and aneurysm formation. Cystic medial degeneration occurs normally to some extent with aging, but the process is accelerated by hypertension (reviewed in Isselbacher E M, Circulation. 2005; 111:816-828.). There are a number of conditions that predispose a person to develop defects of the inner lining of the aorta, including hypertension, Marfan's disease, Ehlers-Danlos syndrome, connective tissue diseases, Turner syndrome, bicuspid aortic valve, Familial Thoracic Aortic Aneurysm Syndrome, and defects of heart development which begin during fetal development. A dissection can also occur accidentally following insertion of a catheter, trauma, or surgery. Abdominal aortic aneurysms (AAAs) affect the part of the aorta in the abdominal cavity. AAA are much more common than thoracic aortic aneurysms. Age is an important risk factor, and the incidence of abdominal aortic aneurysm rises rapidly after the age of 55 years in men and 70 in women. Recent estimates indicate that the prevalence of AAA is 4% to 9% in adults older than 65 years old. AAA is strongly associated with local aortic wall and systemic atherosclerosis, but a clear causal relationship is not established (reviewed in Isselbacher Circulation 2005 and Faxon D P, Circulation. 2004 Jun. 1; 109(21):2617-25). Etiologic factors include genetic susceptibility; 15% to 20% of patients have a family history. AAA is much more common (2 to 5 times) in men than in women and more common in white than black populations. Cigarette smoking is a major risk factor for AAA. The natural history is a gradual enlargement of the aneurysm until it exceeds 5.5 cm, when risk of rupture rises exponentially (Thompson R W, Geraghty P J, Lee J K. Abdominal aortic aneurysms: basic mechanisms and clinical implications. Curr Probl Surg. 2002; 39: 110-230). The primary pathophysiological process is chronic transmural inflammation with destruction of the media, including loss of elastic fibers and SMCs. Elevation of inflammatory markers such as interleukin-6 and elevation of proteinases such as MMP9 and elastin are correlated with AAA and the expansion rate. Doxycycline inhibits MMP activity and can reduce AAA in experimental animals. Clinical trials have shown a reduction in MMP9 levels with doxycycline but not a reduction in expansion rate in preliminary studies. Other agents such as roxithromycin have shown modest effects as well.
Currently, the only available treatments for aortic aneurysm are surgical resection and replacement or more recently, insertion of an endovascular stent. Then, patients are usually given long term treatment with drugs to reduce their hypertension.
Therefore, there is a need to provide new drugs that will help the physician to prevent or treat aortic aneurysm
Furthermore, a major problem in the management of aortic aneurysms is that the symptoms of an aortic aneurysm often do not surface until the aneurysm is quite large. Therefore, a timely diagnosis may be suitable to envisage an early intervention and dramatic improvement in the chances for survival.
However, in both cases, there is a permanent need in the art for seeking animal models for aortic aneurysms to provide insight into potential mechanisms in the development and treatment of disease.
Several mouse models of aortic aneurysms have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction (Daugherty et al. Arterioscler. Thromb Vase Biol. 2004 March; 24(3):429-34). The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Genetic models include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII. For example Daugherty A. et al. (2000) developed a mouse model wherein angiotensin II is continuously infused into mature apoE deficient mice.
However, there is still a need in the art to provide reliable animal models for aortic aneurysm that are reproducible (for example AAA incidence in the AII/ApoE deficient mouse model ranged from 14%, see Babamusta F et al Atherosclerosis. 2006 June; 186(2):282-90, to more than 60%) and do not involve any surgical treatment (unlike elastase or calcium chloride model) to provoke an aneurysm to develop or occur.